Future Challenges
As we look to continue to strengthen both clinical and regulatory protections for children, a number of significant challenges require the attention of paediatricians, pharmacologists, pharmacists and policy makers.
Off Label Use. The regulatory environment for new drug approvals in the United States and the European Union has resulted in an increase in paediatric labelling for new therapeutic entities and a parallel decrease in off-label use (49). This is an important issue. While off-label drug use does occur in adults, this is typically on the basis of new evidence that demonstrates safety and efficacy of drugs for new indications. In contrast, in children off-label drug use has often been on the basis of extrapolation in the absence of firm evidence, and on many occasions has been associated with adverse outcomes. Off label drug use has been identified as a separate and distinct risk factor for adverse drug reactions in children (49, 50).
However, the decrease in off-label use in Europe has been marginal despite these changes (64% post legislative changes versus 58% prior the changes) (50). This is likely due to the fact that the existing regulatory mechanisms address only novel products, and the majority of drug use in children is concentrated in older, often off-patent medications.The best approach to enhancing paediatric labelling and reducing off-label use, notably for older medications, remains unclear.
Child Friendly Formulations. The issue of child-friendly formulations remains an important issue and one that, in pragmatic terms, often“orphans” children from safe and effective therapies (1). Many children under the age of eight and essentially all children under the age of four have difficulty in swallowing conventional tablets. (Interestingly, up to 10% of adults and a higher number of senior citizens report difficulty in swallowing conventional tablets and capsules). Some medications - notably antibiotics – are available in liquid form but for many other medications pharmacists or parents must crush and dissolve or mix medications with flavour masking agents (51). Creating a dosage form in this manner – a practice known as compounding – is a skill that is less and less frequently taught in pharmacy faculties and is often quite variable in approach and technique. Compounding introduces a new series of risks including dose and drug errors. Importantly, compounding also circumvents the carefully designed regulations for Good Manufacturing Practice established to provide safe dosage forms for adults.
There have been a number of innovative approaches to enhance oral drug delivery for children, and while many such as mini-tablets, gel technology and 3D printing onto orodispensible films offer great promise, their uptake has been less rapid and certainly less generalized than desired (52). In the area of child-friendly formulations, European research groups have been among the world leaders (53). However, the dissemination of these formulations beyond Europe and the United States is much at best spotty and certainly less than optimal (47). Work in a number of centres and by a number of regulators is exploring the safety and optimal nature of excipients in paediatric formulations.. Given that children will likely always represent a small market for pharmaceuticals compared to adults, it is likely that this work would benefit substantially form incentives to counterbalance the impact of market forces on the impetus for formulation development.
Design of Clinical Trials in Children. A further regulatory challenge lies in the area of clinical trial design. While regulatory approval has relied heavily on conventional randomized double-blind controlled trials - the “gold standard” for drug approval – this has been problematic for drugs for children, related to issues such as small sample size, selection of appropriate and clinically meaningful outcomes, appropriate instruments for evaluation and suitable safety monitoring (26). To address these issues and to meet the challenges of the new revolution in therapeutics, investigators have developed a number of novel clinical trial designs tailored to the unique problems in paediatric drug research (55-58). Examples of these include adaptive design, in which trial design is changed over the course of a trial based on interim analysis; this is a different approach than the conventional randomized double blind trial and requires meticulous pre-study planning (55). A challenge for drug regulatory agencies is how to best accept the results of these studies for drug approval and to inform product monographs.
Regulatory Harmonization. An additional challenge for drug development in general but for paediatrics in particular is harmonization of requirements and regulations across multiple jurisdictions. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a Swiss-based group that for the past twenty-five years has been working to harmonize the regulatory requirements of multiple jurisdictions. Over the past decade, many jurisdictions have modified their requirements for new drug submissions to better align across international boundaries, and although there has been some success in this area much work remains to be done (54). The frequent and increasing dialogue between the FDA and EMA as to how to encourage drug studies in children is an encouraging development, notably given that regulators for other jurisdictions are involved in these discussions as observers.
Brexit. In addition to global issues there are interesting challenges in how Brexit will impact on paediatric drug development in the UK – which has a number of talented paediatric clinical pharmacologists and some of the best academic child health care centres in Europe – has yet to be determined (59). The UK academic and industrial community and EMA have benefited greatly from close interaction and it is hoped that whatever agreements are negotiated as the UK leaves the European Union can preserve these benefits.
Talent Pool and Pipeline. A challenge and an opportunity is the talent pool of researchers with interest and expertise in conducting drug research in children. The number of investigators is limited and primarily located in developing countries (60). In part this is due to the perception that immediate clinical needs in developing nations may be seen to be a higher priority than the development of drug researchers and is in part due to the fact that promising young investigators who train in the developing world are often attracted to the deeper resources available for research in the developed world. However, there is a cadre of young pharmacologists with interest in moving drug research in children forward and in working together across countries and across regions in creating the critical mass needed to surmount the challenges detailed above.